[ CAS No. 1187594-09-7 ]

{[proInfo.proName]}
Cat. No.: {[proInfo.prAm]}
2D
Chemical Structure| 1187594-09-7
Chemical Structure| 1187594-09-7
Structure of 1187594-09-7

Quality Control of [ 1187594-09-7 ]

Purity: {[proInfo.showProBatch.pb_purity]}

Related Doc. of [ 1187594-09-7 ]

SDS

Product Details of [ 1187594-09-7 ]

CAS No. :1187594-09-7MDL No. :MFCD27920779
Formula :C16H17N7O2SBoiling Point :-
Linear Structure Formula :-InChI Key :-
M.W :371.42Pubchem ID :44205240
Synonyms :

Computed Properties of [ 1187594-09-7 ]

TPSA : 129 H-Bond Acceptor Count : 7
XLogP3 : -0.5 H-Bond Donor Count : 1
SP3 : 0.38 Rotatable Bond Count : 5

Safety of [ 1187594-09-7 ]

Signal Word:WarningClassN/A
Precautionary Statements:P280-P305+P351+P338UN#:N/A
Hazard Statements:H302Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1187594-09-7 ]

  • Upstream synthesis route of [ 1187594-09-7 ]
  • Downstream synthetic route of [ 1187594-09-7 ]

[ 1187594-09-7 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 3680-69-1 ]
  • [ 1187594-09-7 ]
YieldReaction ConditionsOperation in experiment
99% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 80 - 85℃; for 5.00 h; 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (0.8 g; Formula IX) was added into a reaction vessel containing a solution of potassium carbonate (2.1 g) in water (30 mL) at about 20°C to about 25°C. A solution of { l-(ethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]azetidin-3-yl}acetonitrile (2.0 g; Formula V) in 1,4-dioxane (30 mL) was added into the reaction mixture at about 20°C to about 25 °C, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.1 g). The reaction mixture was stirred at about 80°C to about 85°C for about 5 hours. On completion of the reaction, 1,4-dioxane was recovered from the reaction mixture under reduced pressure at about 45°C to obtain a residue. Ethyl acetate (50 mL) was added into the residue, and then the contents were stirred for about 5 minutes. The organic and aqueous layers were separated. The organic layer was concentrated under reduced pressure at about 45°C to obtain baricitinib. Yield: 99.0percent
90% With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In water; toluene; tert-butyl alcohol at 100℃; for 48.00 h; Inert atmosphere Compound 5 (0.092g, 0 . 24mmol), compound 11 (0.037g, 0 . 24mmol), cesium fluoride (0.129g) and Pd (PPh 3) 4 (0.028g) adding toluene, tertiary butyl alcohol and water (1:1:1) in the mixed solvent, nitrogen protection, 100 °C reflux reaction 48 hours, cooling to room temperature, a diatomite filter. Ethyl acetate for flushing diatomite, collect filtrate, separating organic layer, the aqueous layer extracted with ethyl acetate, the organic layer concentrated, drying, column chromatography purification to obtain white solid 0.060g, yield 90percent.
90% With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In tetrahydrofuran; water at 90℃; for 19.00 h; Autoclave; Inert atmosphere 2~yl)-lH-pyrazol-l-yl]azetidm-3-yl}acetonitrile (5.00 g, 13.15 mmol), potassium phosphate tribasic (2.80 g, 13.19 mmol) and a mixture of dichloro[l, - bis(dicyclohexylphosphino)ferrocene] palladium(ll) with potassium phosphate tribasic (2.84 g of the mixture containing 50 mg total with 0.07 mmol palladium catalyst). THF (21 mL) is added to the autoclave followed by water (5.3 mL). The autoclave is sealed and the contents are heated to 90 °C for 19 hours. The reaction mixture is cooled and the resulting suspension is diluted with THF (40 mL) and water (10 mL). The solution is filtered through a mixture of diatomaceous earth (0.4 g) and carbon (0.2 g). The filtrate is concentrated under vacuum to remove THF. An aqueous buffer solution (pH = 7, 30 mL) is added followed by l-butanol (30 mL). The mixture is heated to 85 °C with stirring to dissolve residual solids. Stirring is stopped and the lower aqueous layer is removed. Water (10 mL) is added to the stirred l-butanol layer. Stirring is discontinued and the lower aqueous layer is removed. The l-butanol layer is cooled to 75 °C and stirred for 30 minutes. The solution is further cooled to 20 °C over 6 hours and the resulting slurry is held at that temperature overnight. The solids are collected by filtration, washed with 9: 1 v/v 1 -butane i/water (10 mL) and dried at 40 °C to give the title compound (3.45 g, 70.6percent). The title compound (2.5 g, 6.73 mmol) is combined with l-butanol (12.6 mL) and water (3.8 mL). The mixture is heated to 85 °C and stirred for 30 minutes. The solution is cooled to 20 °C over 7 hours to provide a slurry. The solids are collected by filtration then washed with 1-butanol followed by water. The solids are dried to give the title compound (2.25 g, 90percent after recrystallization of 2.5 g).
84% With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In water; toluene; tert-butyl alcohol for 48.00 h; Reflux; Inert atmosphere To a flask were added 2-{1-(ethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (12) (870 mg, 2.3 mmol, 1.1 equiv.), 4-chloro-7-H-pyrrolo[2,3-d]pyrimidine (5) (290 mg, 0.19 mmol), caesium fluoride (1120 mg), tetrakis(triphenylphosphine)palladium (240 mg, 0.1 equiv.), tertbutanol (10 mL), water (10 mL) and toluene (10 mL) at ambient temperature. The resulting reaction mixture was heated to reflux under nitrogen for 48 h. Then the reaction mixture was cooled to room temperature and filtered through a Celite bed. The Celite bed was washed with ethyl acetate and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure to remove solvents and the crude product was purified by flash chromatography on a silica gel column eluting with methanol in dichloromethane (0–60percent) to afford baricitinib: Yield 560mg (84percent); m.p. 193–195 °C; IR: 3203, 3113, 2998, 2847, 2363, 1584, 1328, 1137 cm–1. Anal. calcd for C16H17N7O2S: C, 51.74; H, 4.61; N, 26.40; found: C, 51.91; H, 4.49; N, 26.57percent. MS (m/z): 372 [M + H]+;1H NMR (300 MHz, DMSO-d6): δ 1.25 (t, J = 7.3 Hz, 3H), 3.23 (m, J= 7.3 Hz, 2H), 3.69 (s, 2H), 4.24 (d, J = 9.0 Hz, 2H), 4.61 (d, J = 9.0 Hz,2H), 7.08 (s, 1H), 7.62 (s, 1H), 8.47 (s, 1H), 8.71 (s, 1H), 8.92 (s, 1H),12.12 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 7.4, 24.9, 39.3, 43.4, 58.5, 99.9, 113.0, 116.6, 126.9, 129.5, 139.9, 149.3, 150.9, 152.2.

Reference: [1] Patent: WO2016/125080, 2016, A2. Location in patent: Page/Page column 12
[2] Patent: CN105541891, 2016, A. Location in patent: Paragraph 0117; 0120; 0121; 0122; 0129; 0130
[3] Patent: WO2016/205487, 2016, A1. Location in patent: Page/Page column 32-33
[4] Journal of Chemical Research, 2016, vol. 40, # 4, p. 205 - 208
  • 2
  • [ 1187595-85-2 ]
  • [ 1187594-09-7 ]
YieldReaction ConditionsOperation in experiment
91.2%
Stage #1: With potassium carbonate In acetonitrile at 20℃; for 0.50 h;
Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 40℃; for 8.00 h;
200 g of acetonitrile and 20.4 g (0.05 mol) of compound 4 were added to a 1 L reaction flask. 6.9 g (0.05 mol) was added with stirring. Potassium carbonate was stirred at room temperature for 30 min, then 9.3 g (0.05 mol) of compound 7 and 8 g (0.05 mol) of DBU were added. The temperature of the system is raised to 40 ° C After the reaction for 8 hours, the reaction was completed, and the reaction of the starting materials was completed, and the reaction was stopped. Evaporate the solvent under reduced pressure and add to the system. After quenching the reaction with 100 g of water, 200 g of ethyl acetate was added. Stir for 30 min, filter, and rinse the cake with 100 g of fresh ethyl acetate. The filter cake was dried to give a white solid of 17.0 g, HPLC ≥ 99.0percent, yield: 91.2percent.
Reference: [1] Patent: CN108129482, 2018, A. Location in patent: Paragraph 0054; 0064; 0065
  • 3
  • [ 3680-69-1 ]
  • [ 1187594-09-7 ]
YieldReaction ConditionsOperation in experiment
73% With palladium diacetate; caesium carbonate; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In N,N-dimethyl acetamide; water at 95 - 100℃; Inert atmosphere A solution of 2-(3-(4-(5,5-dimethyl-1,3,2-dioxaborate-2-yl)-1H-pyrazol-1-yl)-1(ethylsulfonyl)azetidin-3-yl)acetonitrile (36.62 g, 1OO mmol)4-chloro-7H-pyrrolo[2,3-d]pyrimidine (16.12 g, 105 mmol)Cesium carbonate (52.92 g, 150 mmol),N, N-dimethylacetamide (180 mL) and water (36 mL)Stirring dissolved after vacuum switch nitrogen 3 times,Palladium acetate (113 g, 0.5 mmol) was added under nitrogen atmosphere,Ligand XtanPhos(289 mg, 0.5 mmol),And then vacuum switch nitrogen 3 times,Then heated to 95 ~ 100 ° C for 5-6 hours,The reaction was quenched by adding water (180 mL) and the mixture was extracted twice with ethyl acetate (180 mL). The combined organic phase was washed twice with water (180 mL), filtered through celite and concentrated to recrystallize with isopropanol and water Biti products (27. llg, 73percent).
Reference: [1] Patent: CN106946917, 2017, A. Location in patent: Paragraph 0097-0099
  • 4
  • [ 1187595-90-9 ]
  • [ 1187594-09-7 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With water; sodium hydroxide In tetrahydrofuran; methanol at 20℃; for h;
Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water at 20℃; for 0.50 h;
A suspension of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 1.0 g, 2.06 mmol) in methanol (MeOH, 5 mL) and tetrahydrofuran (THF, 20 mL) was treated with a 1 M aqueous sodium hydroxide solution (NaOH, 2.3 mL, 2.3 mmol, 1. 12 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 2-3 h. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and a 1 N aqueous HCl solution (0.2 mL) to adjust pH to 7-7.5 at room temperature. The resulting mixture was stirred at room temperature for 30 min before the solids were collected by filtration. The solids were washed with a mixture of acetonitrile and water (2/3 by volume, 2.x.4 mL) and dried in vacuum at 40-45° for 24 h to afford crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (14, 658 mg, 765 mg theoretical, 86percent yield) as off-white solids, which was found to be identical to the material prepared by Method A. For crude 14: 1H NMR (DMSO-d6, 300 MHz) δ 12.15 (s, 1H), 8.94 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 7.63 (d, 1H), 7.09 (d, 1H), 4.62 (d, 2H), 4.25 (d, 2H), 3.71 (s, 2H), 3.24 (q, 2H), 1.26 (t, 3H) ppm; C16H17N7O2S (MW, 371.42), LCMS (EI) m/e 372 (M++H).
81% With sodium hydroxide In tetrahydrofuran; methanol at 20 - 25℃; for 3.00 h; 4-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (1 g), methanol (5 mL), tetrahydrofuran (20 mL), and 1M sodium hydroxide (2.3 mL) were added into a reaction vessel at 20°C to 25 °C. The reaction mixture was stirred for 3 hours. Progress of the reaction was monitored by thin layer chromatography. On completion, the reaction mixture was quenched by adding water (20 mL). The pH was adjusted to 7.0 to 7.5 by adding IN hydrochloric acid, followed by completely recovering the solvent under reduced pressure at 40°C to 50°C. A sticky material was obtained. Water (10 mL) was added to the sticky material at 20°C to 25°C. The contents were stirred for 10 minutes. A solid material was precipitated out. The solid material was filtered, washed with water (20 mL), and then dried under reduced pressure at 40°C to 45°C for 24 hours to obtain the amorphous form of baricitinib. Yield: 81percent.
Reference: [1] Patent: US2009/233903, 2009, A1. Location in patent: Page/Page column 69
[2] Patent: WO2015/145286, 2015, A1. Location in patent: Page/Page column 7
[3] Patent: CN108341818, 2018, A. Location in patent: Paragraph 0053-0054
  • 5
  • [ 1187594-13-3 ]
  • [ 1187594-09-7 ]
YieldReaction ConditionsOperation in experiment
83.8%
Stage #1: With lithium tetrafluoroborate; water In acetonitrile at 75℃;
Stage #2: With ammonium hydroxide; water In acetonitrile at 0 - 10℃;
To a solution of 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (6, 327 g, 655 mmol) in acetonitrile (3 L) and water (300 mL) was added LiBF4 (614 g, 6.55 mol, 10.0 equiv). The resulting reaction mixture was stirred at 75° C. for overnight. The reaction mixture was cooled to 0° C. before a solution of ammonium hydroxide (NH4OH, 570 mL) in water (2.2 L) was added slowly to keep the temperature below 10° C. (pH 9-10). The mixture was stirred at room temperature for overnight. When the reaction was deemed complete, water (10 L) was added and the resulting mixture was vigorously stirred for 3 h at room temperature. The solids were collected by filtration, washed with water (6.7 L) and heptane (6.7 L), and dried in vacuum oven at 45° C. over the weekend. The dried solid was then dissolved in 20percent MeOH in dichloromethane (12 L), and was purified by column chromatography on 1.3 Kg of silica gel eluting with a 20percent MeOH in dichloromethane solution (18L) to afford 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (7, 204 g, 243.3 g theoretical, 83.8percent yield) as an off-white solid. For 7: 1H NMR (300 MHz, d6-DMSO) δ 1.25 (t, 3H), 3.25 (q, 2H), 3.75 (s, 2H), 4.25 (d, 2H), 4.65 (d, 2H), 7.10 (d, 1H), 7.65 (dd, 1H), 8.50 (s, 1H), 8.70 (s, 1H), 8.95 (s, 1H), 12.2 (bs, 1H); MS: m/z calcd. 372.12; found: 372.0.
Reference: [1] Patent: US2009/233903, 2009, A1. Location in patent: Page/Page column 58; 60
  • 6
  • [ 1187595-85-2 ]
  • [ 1187594-09-7 ]
Reference: [1] Patent: CN105541891, 2016, A
[2] Patent: WO2016/205487, 2016, A1
[3] Patent: WO2016/205487, 2016, A1
[4] Patent: CN106496195, 2017, A
[5] Patent: CN106496195, 2017, A
[6] Patent: CN106496195, 2017, A
[7] Patent: CN106496195, 2017, A
[8] Patent: CN106496195, 2017, A
[9] Patent: CN106946917, 2017, A
[10] Patent: CN106946917, 2017, A
[11] Patent: CN106946917, 2017, A
  • 7
  • [ 3680-69-1 ]
  • [ 1187594-09-7 ]
Reference: [1] Patent: WO2016/205487, 2016, A1
[2] Patent: CN107176955, 2017, A
[3] Patent: CN108129482, 2018, A
  • 8
  • [ 1153949-11-1 ]
  • [ 1187594-09-7 ]
Reference: [1] Journal of Chemical Research, 2016, vol. 40, # 4, p. 205 - 208
[2] Patent: CN105541891, 2016, A
  • 9
  • [ 186519-89-1 ]
  • [ 1187594-09-7 ]
Reference: [1] Patent: CN107176955, 2017, A
  • 10
  • [ 1236033-21-8 ]
  • [ 1187594-09-7 ]
Reference: [1] Patent: CN108129482, 2018, A
Related Products
Historical Records